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from start of study drug administration. Dose escalation
decision and recommended dose (RD) were made by an
independent safety committee. Blood PK and PD samples
were serially drawn along the 3 cycles.
Results:
Fourteen patients were included in the study. DLTs
per dose level (DL) are shown in the table with 3 patients
experiencing more than one DLT. The RD of Debio 1143 to be
combined with CRT was 200 mg/day (=MTD). Debio 1143
exposure increased proportionally with dose and did not
accumulate over time. Amylase/lipase and ALT/AST increase
was associated with higher Debio 1143 exposures. At all dose
levels, the PD effect of Debio 1143 was evidenced by the
degradation of cIAP1 in PBMCs and a trend in an increase of
serum MCP1. 12 patients were evaluable for response by
RECIST 10-12 weeks post treatment among which 3 CR, 5 PR
and 1 SD.
Conclusion:
Combination of Debio 1143 with CRT was
tolerated, exhibited favourable PK in combination with CRT
with significant PD activity. The MTD was found to be 200
mg/day and is now being used in a randomized phase 2 study
initiated by GORTEC to evaluate the anti-tumor activity of
this combination in LA-SCCHN.
PV-0519
The hypoxic radiosensitizer, nimorazole, in RT of HNSCC:
pharmacokinetics, toxicity and compliance
M.A.H. Metwally
1
Aarhus University Hospital, Department of Experimental
Clinical Oncology, Aarhus C, Denmark
1
, J. Overgaard
1
Purpose or Objective:
Study of pharmacokinetics (PK),
toxicity, and compliance with nimorazole (NIM) which is
currently investigated for its efficacy in three large
randomized clinical trials (NIMRAD, EORTC 1219/DAHANCA
29, and DAHANCA 30)
Material and Methods:
The PK of NIM was studied in 63
patients with HNSCC treated in the DAHANCA-5 trial. While
the toxicity and compliance were studied in HNSCC patients
treated with NIM, in combination with radiotherapy (RT) or
chemo-radiotherapy (CRT), in Denmark between 1990 and
2013. Plasma concentration measurements were done using
high pressure liquid chromatography following the first day
dose; and plasma concentration profiles were subjected to
non-compartmental PK analysis using validated PC-based
software. The different PK parameters were calculated and
correlated with the different patient- and treatment-related
variables. Nimorazole was administered as oral tablets in
doses of approximately 1.2 g/m² BSA before the first daily
radiation treatment. A second dose of 1 g was given before
the second RT fraction in the accelerated fractionation
regimen (6 fractions/week). The compliance was estimated
as the percentage of the initially prescribed dose; and drug-
related side effects were reported from the DAHANCA
database.
Results:
A linear relationship between peak plasma
concentration and administered dose was detected. The
mean peak concentration was 36.8 ± 1.3 µg/ml, and the time
of peak concentration ranged between 30 and 180 min
(median 60 min). Plasma elimination occurred with a mean
half-life of 3.35 ± 0.09 h. There was a statistically significant
correlation between area under the concentration-time curve
(mean 191 ± 6 µg·h/ml) and administered dose, especially
when expressed as g/m². A statistically significant longer
elimination half-life in men relative to women (mean
difference 0.40 h; 95% confidence interval 0.77-0.03; P 0.03)
was detected. A total of 1049 patients were investigated for
toxicity and compliance with NIM. The compliance was fair,
with both conventional and accelerated RT as well as CRT
schedules, with 58% of patients received the full prescribed
total dose. Nausea and vomiting were the major complaints
representing 87% of the known side effects that caused dose
reduction. All side effects ceased when treatment was
interrupted, and neither severe nor long lasting side effects
were observed. Female patients, and patients received
accelerated CRT were significantly less compliant with NIM,
and more likely to have nausea and vomiting; while patients
who received less than 1100 mg/m² per day were
significantly more compliant, and less likely to have nausea
and vomiting.
Conclusion:
The current nimorazole administration practice
in clinical trials is acceptable, and the compliance to the
drug is fair, either with the conventional or accelerated RT as
well as CRT, with tolerable acute, but neither persistent nor
late, toxicity.
Symposium: Dose painting: those pending issues
SP-0520
The promises of dose painting
W. De Neve
1
De Neve Wilfried, Belgium,
1
, L. Veldeman
2
, P. Ost
2
, F. Duprez
2
, K.
Vandecasteele
2
, K. De Wolf
3
, C. Monten
2
, D. Berwouts
4
,
A.M.L. Olteanu
2
, T. Vercauteren
2
, W. De Gersem
2
2
University Hospital Ghent, Radiation-Oncology, Ghent,
Belgium
3
Ghent University, Radiation-Oncology, Ghent, Belgium
4
University Hospital Ghent, Radiology, Ghent, Belgium
Purpose To demonstrate that dose painting (DP) is a
promising tool to decrease overall treatment time (OTT), to
reduce toxicity, to improve palliation or enhance tumor
control. The present state of DP will be illustrated through 3
types of applications. We will also speculate about the
potential of DP to integrate with novel systemic treatment
approaches.
Materials and methods
A. Topographical DP (TDP) in breast irradiation. TDP
distributes dose as function of the spatial distribution of
subclinical cancer deposits nearby the primary tumor in
breast cancer. Patients (n=170) were randomized between
prone whole breast irradiation (WBI) followed by a boost
(WBI-SeqB: OTT=4 weeks) and WBI with simultaneous
integrated boost (SIB) using TDP (WBI-TDP-SIB: OTT=3
weeks). Acute moist desquamation rate was the primary
endpoint.
B. DP against bone metastasis pain. There is no dose-response
relationship above 8 Gy single dose for the control of pain by
uncomplicated bone metastases. This observation triggered
the hypothesis that cytokine cascades counteracting
palliation are activated by radiation and that their activity is
function of the irradiated volume. DP was employed to
drastically reduce the irradiated volume. Patients (n=45)
were randomly assigned (1:1:1) to receive a single fraction of
either 8 Gy with conventional radiotherapy (Conv-8Gy) or 8
Gy with DP (dose range 6-10 Gy) (DP-8Gy) or 16 Gy with DP
(dose range 14-18 Gy) (DP-16Gy). The trial was designed for
selection of the experimental arm worthwhile of continuing
in phase III.
C. DP in loco-regionally advanced head&neck cancer. 18F-
FDG-PET-guided DP-treated patients enrolled in 3 dose-
escalation studies (n = 72) were matched with standard IMRT-
treated patients (n=72) irradiated during the same time
period. Median dose in the DP-group was 70.2-85.9 Gy/30-32